Dataset Information

Mosaicism and incomplete penetrance of PCDH19 mutations.

ABSTRACT: BACKGROUND:Mutations in the PCDH19 gene have mainly been reported in female patients with epilepsy. To date, PCDH19 mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism. OBJECTIVE:We aimed to investigate the occurrence of mosaic PCDH19 mutations in 42 families comprising at least one patient with PCDH19-related epilepsy. METHODS:Two male patients with mosaic PCDH19 variants were identified using targeted next-generation sequencing. Forty female patients with PCDH19 variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with PCDH19 variants. RESULTS:Five mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred PCDH19 variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%. CONCLUSION:Our study provides new insights into phenotype-genotype correlations in PCDH19 related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.

SUBMITTER: Liu A

PROVIDER: S-EPMC6581080 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Mosaicism and incomplete penetrance of <i>PCDH19</i> mutations.

Liu Aijie A Yang Xiaoxu X Yang Xiaoling X Wu Qixi Q Zhang Jing J Sun Dan D Yang Zhixian Z Jiang Yuwu Y Wu Xiru X Wei Liping L Zhang Yuehua Y

Journal of medical genetics 20181004 2

<h4>Background</h4>Mutations in the <i>PCDH19</i> gene have mainly been reported in female patients with epilepsy. To date, <i>PCDH19</i> mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.<h4>Objective</h4>We aimed to investigate the occurrence of mosaic <i>PCDH19</i> mutations in 42 families comprising at least one patient with <i>PCDH19</i>-related epilepsy.<h4>Methods</h4>Two male patients with mosaic <i>PCDH19</i> variants were i ...[more]

PMID: 30287595

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Project description:The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as "dual molecular diagnosis." The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.

Dataset Information

Mosaicism and incomplete penetrance of PCDH19 mutations.

Publications

Mosaicism and incomplete penetrance of <i>PCDH19</i> mutations.

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